Nucleoside analogues: mechanisms of drug resistance and reversal strategies

Leukemia (2001) 15, 875890

2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00www.nature.com/leuREVIEWNucleoside analogues: mechanisms of drug resistance and reversal strategiesCM Galmarini1, JR Mackey2 and C Dumontet1,31Unite INSERM 453, Laboratoire de Cytologie Analytique, Faculte de Medecine Rockefeller, Lyon, France; 2Medical and Experimental

Oncology, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada; and 3Service dHematologie, Centre Hospitalier LyonSud, FranceNucleoside analogues (NA) are essential components of AML

induction therapy (cytosine arabinoside), effective treatments

of lymphoproliferative disorders (fludarabine, cladribine) and

are also used in the treatment of some solid tumors

(gemcitabine). These important compounds share some general common characteristics, namely in terms of requiring

transport by specific membrane transporters, metabolism and

interaction with intracellular targets. However, these compounds differ in regard to the types of transporters that most

efficiently transport a given compound, and their preferential

interaction with certain targets which may explain why some

compounds are more effective against rapidly proliferating

tumors and others on neoplasia with a more protracted evolution. In this review, we analyze the available data concerning

mechanisms of action of and resistance to NA, with particular

emphasis on recent advances in the characterization of nucleoside transporters and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to these

compounds. We performed an extensive search of published

in vitro and clinical data in which the levels of expression of

nucleoside-activating or inactivating enzymes have been correlated with tumor response or patient outcome. Strategies aiming to increase the intracellular concentrations of active compounds are presented. Leukemia (2001) 15, 875890.

Keywords: nucleoside analogues; nucleoside transporters; 59-nucleotidase; drug resistanceIntroductionNucleoside analogues (NA) constitute an important class of

antimetabolites used in the treatment of hematological malignancies and, more recently, in solid tumors.1 These therapeutic compounds mimic physiological nucleosides in terms

of uptake and metabolism and are incorporated into newly

synthesized DNA resulting in synthesis inhibition and chain

termination. Some of these drugs also inhibit key enzymes

involved in the generation of the purine and pyrimidine

nucleotides and RNA synthesis, and directly activate the

caspase cascade. All of these effects may lead to cell death.The NA family includes various pyrimidine and purine analogues. Among the pyrimidine analogues cytosine arabinoside

(ara-C, cytarabine) is extensively used in the treatment of

acute leukemia, while gemcitabine has...